Therapeutic inhibitor of vascular smooth muscle cells

• US 6,074,659 A
• Filed: 07/10/1998
• Issued: 06/13/2000
• Est. Priority Date: 09/27/1991
• Status: Expired due to Fees

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: Noerx Corporation
• Inventors: Anderson, Peter G., Grainger, David J., Kunz, Lawrence L., Reno, John M., Metcalfe, James C., Klein, Richard A., Weissberg, Peter L.
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US09/113,733
• Time in Patent Office: 704 Days
• Field of Search: 514/441, 514/449, 514/773, 424/423, 424/424, 424/425
• US Class Current: 424/423
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6831 Fungal toxins, e.g. alpha sarcine, mitogillin, zinniol or restrictocin
• CPC Class Codes: A61K 47/6843 the antibody targeting a material from animals or humans
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 47/6931 the material constituting the nanoparticle being a polymer
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: G01N 2800/323 Arteriosclerosis, Stenosis

Abstract

Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent. Also discussed are mechanisms for in vivo vascular smooth muscle cell proliferation modulation, agents that impact those mechanisms and protocols for the use of those agents.

Claims

1. A therapeutic method, comprising treating procedural vascular trauma associated with placement of a device in a vessel by administering to a mammal a cytostatic amount of an agent that does not exhibit substantial cytotoxicity, wherein the agent is a cytoskeletal inhibitor.

2. The method of claim 1 wherein the agent inhibits microtubules.

3. The method of claim 1 wherein the agent inhibits microfilaments.

4. The method of claim 1 wherein the agent inhibits actin polymerization.

5. The method of claim 1 wherein the agent is a cytochalasin or an analog thereof.

6. The method of claim 5 wherein cytochalasin is administered.

7. The method of claim 5 wherein an analog of cytochalasin is administered.

8. The method of claim 1 wherein the administration is local.

9. The method of claim 1 wherein the administration is systemic.

10. The method of claim 1 wherein the administration is before, during or after the trauma.

11. The method of claim 1 wherein the administration is during the trauma.

12. The method of claim 8, 10, or 11 wherein the delivery is accomplished by the device.

13. The method of claim 12 wherein the delivery is accomplished by a catheter.

14. The method of claim 1 wherein the amount is effective to inhibit migration of vascular smooth muscle cells.

15. The method of claim 12 wherein cytochalasin or an analog thereof is administered.

16. The method of claim 1 wherein the amount is effective to inhibit proliferation of vascular smooth muscle cells.

17. The method of claim 1 or 11 wherein the agent is administered in a sustained release dosage form.

18. The method of claim 17 wherein the agent is administered in a polymeric carrier.

19. The method of claim 11 wherein the sustained release dosage form is biodegradable.

20. The method of claim 1 or 8 wherein the agent is administered in a sustained release dosage form and delivered by the device.

21. The method of claim 17 wherein the sustained release form comprises a binding peptide or protein which specifically binds to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.

22. The method of claim 2 wherein the sustained release dosage form comprises microparticles or nanoparticles.

23. The method of claim 22 wherein the sustained release dosage form comprises a polymer derived from the condensation of alpha-hydroxycarboxylic acids and related lactones.

24. The method of claim 23 wherein the polymer is selected from the group consisting of a polylactide, a polyglycolide, and a copolymer of lactide and glycolide subunits.

25. The method of claim 24 wherein the polymer is poly(lactide co-glycolide).

26. The method of claim 1 or 21 the vessel is subjected to angioplasty, placement of a stent, or grafting.